nobody
nothing

2019-02-13 18:58

Posting: # 19907
Views: 1,141
 

 Dabigatran EMA - product-specific guide [Regulatives / Guidelines]

Hi again!

Just by chance I stumbled upon this here:

https://www.ema.europa.eu/en/dabigatran-etexilate-product-specific-bioequivalence-guidance

Have a look at the comments by the originator and the final guidance. OK, pH and dabigatran is an issue, but is it really sufficient that the originator writes some 15-20 lines of text (without any citation?) to introduce a rather complex study to the development of a generic? No data at all supporting this claim? And EMA just buys it? Are we back to the 1950's?

Or all data trade secrets? OMG... reminds me of some witch hunt before the inquisition started to introduce some legal procedures before the death penalty was imposed.



Sorry, too late for "edit", but this might be a clear case for a publication in the Journal "Well, trust us"...

http://www.sciencemag.org/careers/2012/02/ive-got-your-impact-factor-right-here

:-(


Edit: normally you should have been able to edit your message ? You have 24 hours to do so. No time limit for Mods and Admins, luckily :-) [Ohlbe]

Kindest regards, nobody
ElMaestro
★★★

Denmark,
2019-02-13 22:59

@ nobody
Posting: # 19910
Views: 1,035
 

 Dabigatran EMA - product-specific guide

Hi nobody,


» http://www.sciencemag.org/careers/2012/02/ive-got-your-impact-factor-right-here

Thanks for this link.
"And the Journal of Negative Results in Homeopathy is the entire field of homeopathy." :-D:-D:-D:-D:-D:-D:-D:-D:-D:-D:-D

Best day ever.

I could be wrong, but...
Best regards,
ElMaestro
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2019-02-14 00:24

@ ElMaestro
Posting: # 19911
Views: 1,029
 

 OT: A major loss

[image][image]Hi ElMaestro & nobody,

too bad that the Journal of Negative Results in Bio­medicine ceased to be published.

I like (seriously!) this one:

Hammami MM, Yusuf A, Shire FS, Hussein R, Al-Swayeh R. Does the placebo effect modulate drug bio­avail­ability? Randomized cross-over studies of three drugs. J Negat Results Biomed. 2017;16(1):10. doi:10.1186/s12952-017-0075-2. [image] free resource.

I’ll send it to my friends at HC stating in the guidance Section 2.4.2:

To avoid study bias [sic], comparative bioavailability studies should be conducted in such a way that the subjects are not aware of which product (test or reference) is being administered.


Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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nobody
nothing

2019-02-14 09:31

@ Helmut
Posting: # 19914
Views: 1,001
 

 OT: A major loss

Hi Hellcourage!

Yeah, but the outcome of the study was, sorry to say, negative. ;-)

@TheManWithTheFence: My favourite is "The Literature" so you can say you studied thoroughly The Literature. :-D

Nobody joins nobodies furor on this EMA thing? Quite normal to you?

PS: Ohlbe, you'R right, I missed the button for "Edit", simply it's normally over/under your post in any recent forum software. Sorry for that, thank'S for your service! :-)

Kindest regards, nobody
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2019-02-14 11:37

@ nobody
Posting: # 19915
Views: 966
 

 OT: A major loss

Hi nobody,

» Yeah, but the outcome of the study was, sorry to say, negative. ;-)

Quotes from:
  • Participants
    A written “consent” (specific to the drug to be administered) was obtained from each volunteer; being told that the study compares the effects of tablets/capsules containing placebo to those containing the particular drug on a new serum marker, that it aims to determine how much of the observed changes in the serum marker is not related to the particular drug, and that they will each receive both the drug and placebo in a random sequence. At the completion of the three studies […], the volunteers were contacted for debriefing on the actual study aim and design and for delayed full consenting.
  • Procedures and intervention
    To enhance the placebo effect, immediately before drug administration, the volunteers were individually briefed and requested to read and sign an additional “consent” document that stated: “As you know, we are doing this study to determine how much of the change in serum marker level that occurs after ingestion of (name and dose of drug) is not related to (name of drug) effect but to placebo effect. This study has two parts. One time you will take (name of drug) and one time you will take a placebo. The placebo is not known to affect the level of the marker. Today you are assigned to take (name of drug or placebo).” Overt drugs were dispensed from the original brand manufacturer bottle, whereas covert drugs were dispensed from a bottle labelled “placebo”.
At the end “BE” was shown for the three drugs. Only Cmax of ibuprofen wasn’t cause the study was underpowered even for a T/R-ratio of 1. You are right that the study didn’t address the issue of blinded / open directly. In BE that would require a double-dummy technique, which is not acceptable cause it may delay absorption.

» @TheManWithTheFence: My favourite is "The Literature" so you can say you studied thoroughly The Literature. :-D

Äh, wer?

» […] I missed the button for "Edit", simply it's normally over/under your post …

As designed and described.

» … in any recent forum software.

Last update on Feb 10th. :-D

[image]If you want to have the edit-link below your post, change your preference to thread view in your profile. I could move it to the top but that’s a lot of coding (up to five links for mods / admins) and nobody [pun] except you complained so far. A f**ing lot of coding to change the link to a button.
I will definitely not move it from the left bar in mix view.

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
nobody
nothing

2019-02-14 13:40

@ Helmut
Posting: # 19919
Views: 947
 

 OT: A major loss

» Hi nobody,
»
» » Yeah, but the outcome of the study was, sorry to say, negative. ;-)
»

»
» » @TheManWithTheFence: My favourite is "The Literature" so you can say you studied thoroughly The Literature. :-D
»
» Äh, wer?

https://www.zdf.de/nachrichten/heute/daenemark-baut-aus-angst-vor-schweinepest-zaun-an-grenze-zu-deutschland-100.html

btw. I passed by Kolding to the east recently (Autobahn full) and while riding the countryside I saw a green Birdsong beer (?) truck. Must have been pretty close to you but forgot (again) your credentials, so no unannounced inspection of computers and coffee machines...

» » […] I missed the button for "Edit", simply it's normally over/under your post …
»
» As designed and described.
»
» » … in any recent forum software.
»
» Last update on Feb 10th. :-D
»
» [image]If you want to have the edit-link below your post, change your preference to thread view in your profile. I could move it to the top but that’s a lot of coding (up to five links for mods / admins) and nobody [pun] except you complained so far. A f**ing lot of coding to change the link to a button.
» I will definitely not move it from the left bar in mix view.

:-p

Kindest regards, nobody
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2019-02-14 12:12

@ nobody
Posting: # 19916
Views: 972
 

 Dabigatran EMA - product-specific guide

Hi nobody,

» Have a look at the comments by the originator and the final guidance.
» OK, pH and dabigatran is an issue, …

Highly variable in fasted but not in fed state.

» … but is it really sufficient that the originator writes some 15-20 lines of text (without any citation?) to introduce a rather complex study to the development of a generic? No data at all supporting this claim? And EMA just buys it? Are we back to the 1950's?

Aren’t you notoriously shouting “It’s the originator, stupid…”?
I’m more concerned about the first footnote in the guidance

* As intra-subject variability of the reference product has not been reviewed to elaborate this product-specific bioequivalence guideline, it is not possible to recommend at this stage the use of a replicate design to demonstrate high intra-subject variability and widen the acceptance range of Cmax. If high intra-individual variability (CVintra > 30 %) is expected, the applicants might follow respective guideline recommendations.

meaning that one can plan for the EMA’s method of reference-scaling. Was the EMA’s PKWP not aware of the the FDA’s guidance?

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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nobody
nothing

2019-02-14 13:34

@ Helmut
Posting: # 19918
Views: 947
 

 Dabigatran EMA - product-specific guide

» Highly variable in fasted but not in fed state.

Hm, here we talk about solubility over relevant pH range. Only good solubility in acidic range, but... see Samant, 2018 on ribociclib. Solubility in aqueous media is only half the story.

» Aren’t you notoriously shouting “It’s the originator, stupid…”?

Could you elaborate on this. No clue what this might mean. If you want a duel, choose your weapon
:hungry:

» I’m more concerned about the first footnote in the guidance

* As intra-subject variability of the reference product has not been reviewed to elaborate this product-specific bioequivalence guideline, it is not possible to recommend at this stage the use of a replicate design to demonstrate high intra-subject variability and widen the acceptance range of Cmax. If high intra-individual variability (CVintra > 30 %) is expected, the applicants might follow respective guideline recommendations.

meaning that one can plan for the EMA’s method of reference-scaling. Was the EMA’s PKWP not aware of the the FDA’s guidance?

Narrow therapeutic range... maybe in the USA. In the EU there are no mass tort trials...

What buys you the widening for Cmax, when both parameters are highly variable? :confused:

Kindest regards, nobody
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2019-02-14 13:52

@ nobody
Posting: # 19920
Views: 931
 

 Dabigatran EMA - product-specific guide

Hi nobody,

» » Aren’t you notoriously shouting “It’s the originator, stupid…”?
» Could you elaborate on this. No clue what this might mean.

See there.

» If you want a duel, choose your weapon
» :hungry:

Surströmming?

» » I’m more concerned about the first footnote in the guidance […]. Was the EMA’s PKWP not aware of the the FDA’s guidance?
»
» Narrow therapeutic range... maybe in the USA. In the EU there are no mass tort trials...

I don’t like the idea that someone widens the limits for this stuff.

» What buys you the widening for Cmax, when both parameters are highly variable? :confused:

Business as usual in all jurisdictions following the EMA’s strange approoach (i.e., WHO; ASEAN States, Australia, Brazil, Egypt, the Russian Federation, the Eurasian Economic Union, New Zealand). At least the WHO initiated a pilot phase for scaling the AUC. For HC widening the limits for AUC is acceptable (no big deal for Cmax; only the PE within 80.0–125.0%).

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
nobody
nothing

2019-02-14 15:01

@ Helmut
Posting: # 19921
Views: 928
 

 Dabigatran EMA - product-specific guide

» » » Aren’t you notoriously shouting “It’s the originator, stupid…”?
» » Could you elaborate on this. No clue what this might mean.
»
» See there.

yeah, but you need irony tags in here,don'T you?

» » If you want a duel, choose your weapon
» » :hungry:
»
» Surströmming?

No chemical weapons.

» » » I’m more concerned about the first footnote in the guidance […]. Was the EMA’s PKWP not aware of the the FDA’s guidance?
» »
» » Narrow therapeutic range... maybe in the USA. In the EU there are no mass tort trials...
»
» I don’t like the idea that someone widens the limits for this stuff.

...maybe we will never see such generics in our lifetime. Wait and see...

Kindest regards, nobody
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